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Chapter 21: The Lymphatic and Immune Systems

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1 Chapter 21: The Lymphatic and Immune Systems
(Image by Volker Brinkman and Abdul Hakkim).

2 Outline Lymphatic overview Immune system Non-specific response
Disorders of the immune system

3 Why Immune with Lymphatic?
What is the connection between the immune and lymphatic systems? Lymphatic system Fluid recovery Immunity Lipid absorption

4 Functions of Lymphatic System
Fluid recovery fluid continually filters from the blood capillaries into the tissue spaces 15% (2 – 4 L/day) of the water and about half of the plasma proteins enters lymphatic system and then returned to the blood Immunity excess filtered fluid picks up foreign cells and chemicals from the tissues passes through lymph nodes where immune cells stand guard against foreign matter activate a protective immune response Lipid absorption lacteals in small intestine absorb dietary lipids that are not absorbed by the blood capillaries

5 Components of the Lymphatic System
Recovered fluid Clear, colorless, similar to plasma Lymphatic vessels Transport lymph Lymphatic cells B and T lymphocytes, NK cells, macrophages, dendritic cells, and reticular cells Lymphatic tissues Aggregates of lymphocytes and macrophages that populate many organs in the body Diffuse lymphatic tissue (MALT), Lymphatic nodules Lymphatic organs High concentration of defense cells Separated by connective tissue capsules Red bone marrow, thymus, lymph nodes, tonsils, and spleen

6 Lymph and Lymphatic Capillaries
Lymphatic capillaries (terminal lymphatics) penetrate nearly every tissue of the body absent from central nervous system, cartilage, cornea, bone and bone marrow sacs of thin endothelial cells that loosely overlap each other cells tethered to surrounding tissue by protein filaments gaps large enough to allow bacteria and cells entrance Endothelium creates valve-like flaps Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display

7 Lymphatic Vessels Converge into larger and larger vessels
Larger ones composed of three layers tunica interna: endothelium and valves tunica media: elastic fibers, smooth muscle tunica externa: thin outer layer Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display

8 Route of Lymph Flow lymphatic capillaries
collecting vessels: course through many lymph nodes six lymphatic trunks: drain major portions of body Jugular, subclavian, bronchomediastinal, intercostal, intestinal, lumbar two collecting ducts: right lymphatic duct – receives lymph from right arm, right side of head and thorax; empties into right subclavian vein thoracic duct - larger and longer, begins as a prominent sac in abdomen called the cisterna chyli; receives lymph from below diaphragm, left arm, left side of head, neck, and thorax; empties into left subclavian vein subclavian veins

9 The Fluid Cycle Figure 21.5 Figure 21.1
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Lymphatic system Cardiovascular system Lymphatic capillaries Cervical lymph nodes Palatine tonsil Pulmonary circuit L. internal jugular v. R. lymphatic duct Thoracic duct Lymph nodes Thymus Lymphatic trunks Axillary lymph node Subclavian vein Collecting duct Thoracic duct Cisterna chyli Spleen R. and l. lumbar trunks Abdominal, intestinal, and mesenteric lymph nodes Intestinal trunk Superior vena cava Collecting vessels Red bone marrow Inguinal lymph nodes Blood flow Popliteal lymph nodes Lymph flow Systemic circuit Lymphatic vessels Lymphatic capillaries Figure 21.5 Figure 21.1

10 Histology of Red Bone Marrow
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Sinusoid Capillary Adipose cell Artery Platelets and blood cell entering circulation Sinusoid Endothelial cells Figure 21.9 Reticular cells Megakaryocyte Central longitudinal vein Sinusoid

11 Thymus thymus – member of the endocrine, lymphatic, and immune systems
houses developing lymphocytes secretes hormones regulating their activity fibrous capsule gives off trabeculae (septa) that divide the gland into several lobes lobes have cortex and medulla populated by T lymphocytes reticular epithelial cells seal off cortex from medulla forming blood-thymus barrier produce signaling molecules thymosin, thymopoietin, thymulin, interleukins, and interferon Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display

12 Histology of Thymus Figure 21.10b Trabecula Trabecula Cortex Medulla
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Trabecula Trabecula Cortex Medulla Lobule (b) © The McGraw-Hill Companies/Rebecca Gray, photographer/Don Kincaid, dissections Figure 21.10b

13 Lymph Node Lymph nodes – most numerous lymphatic organs
two functions: cleanse the lymph act as a site of T and B cell activation Enclosed with fibrous capsule with trabeculae that divide interior into compartments stroma of reticular fibers and reticular cells Parenchyma divided into cortex and medulla germinal centers where B cells multiply and differentiate into plasma cells Cervical, axillary, thoracic, abdominal, intestinal and mesenteric, inguinal, and popliteal

14 Lymph Node Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Stroma: Capsule Medullary cords Reticular tissue Medullary sinus Trabecula Macrophage Trabecula Lymphocytes Cortex Reticular fibers Subcapsular sinus Lymphatic nodule Artery and vein Venule Germinal center Cortical sinuses (b) Medulla Medullary sinus Efferent lymphatic vessel Medullary cord Afferent lymphatic vessels (a) Figure 21.12a,b

15 Lymphadenopathy lymphadenopathy - collective term for all lymph node diseases lymphadenitis - swollen, painful node responding to foreign antigen lymph nodes are common sites for metastatic cancer swollen, firm and usually painless

16 Tonsils tonsils – patches of lymphatic tissue located at the entrance to the pharynx guard against ingested or inhaled pathogens each covered with epithelium have deep pits – tonsillar crypts lined with lymphatic nodules – tonsillitis and tonsillectomy three main sets of tonsils palatine tonsils pair at posterior margin of oral cavity most often infected lingual tonsils pair at root of tongue pharyngeal tonsil (adenoid) single tonsil on wall of nasopharynx Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

17 The Tonsils Figure 21.13 a Pharyngeal tonsil Palate Palatine tonsil
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Pharyngeal tonsil Palate Palatine tonsil Figure a Lingual tonsil (a)

18 Spleen spleen – the body’s largest lymphatic organ
parenchyma exhibits two types of tissue: red pulp - sinuses filled with erythrocytes white pulp - lymphocytes, macrophages surrounding small branches of splenic artery functions blood production in fetus blood reservoir ‘erythrocyte graveyard’ - RBC disposal white pulp monitors blood for foreign antigens spleen highly vascular and vulnerable to trauma and infection ruptured spleen - splenectomy

19 Spleen Figure 21.14a Figure 21.14b Figure 21.14c Diaphragm Spleen
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Diaphragm Spleen Spleen Splenic artery Splenic vein Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Pancreas Superior Kidney Inferior vena cava Gastric area Aorta Common iliac arteries Hilum (a) © The McGraw-Hill Companies/Dennis Strete, photographer Renal area Figure 21.14a Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Splenic vein Splenic artery Red pulp Central artery (branching) (b) Inferior Figure 21.14b White pulp (c) Figure 21.14c © The McGraw-Hill Companies, Inc./Photo by Dr. Alvin Telser

20 Defenses Against Pathogens
pathogens – environmental agents capable of producing disease infectious organisms, toxic chemicals, and radiation three lines of defenses against pathogens: first line of defense – external barriers, skin and mucous membranes second line of defense – several nonspecific defense mechanisms leukocytes and macrophages, antimicrobial proteins, immune surveillance, inflammation, and fever effective against a broad range of pathogens third line of defense – the immune system defeats a pathogen, and leaves the body of a ‘memory’ of it so it can defeat it faster in the future

21 External Barriers skin mucous membranes subepithelial areolar tissue
makes it mechanically difficult for microorganisms to enter the body too dry and nutrient-poor to support microbial growth defensins – peptides that kill microbes by creating holes in their membranes acid mantle – thin film of lactic acid from sweat inhibits bacterial growth mucous membranes digestive, respiratory, urinary, and reproductive tracts are open to the exterior and protected by mucous membranes mucus physically traps microbes lysozyme - enzyme destroys bacterial cell walls subepithelial areolar tissue viscous barrier of hyaluronic acid hyaluronidase - enzyme used by pathogens to make hyaluronic acid less viscous

22 Leukocytes and Macrophages
phagocytes – phagocytic cells with a voracious appetite for foreign matter five types of leukocytes neutrophils eosinophils basophils monocytes lymphocytes

23 Neutrophils wander in connective tissue killing bacteria
phagocytosis and digestion produces a cloud of bactericidal chemicals NETs create a killing zone degranulation lysosomes discharge into tissue fluid respiratory burst – neutrophils rapidly absorb oxygen toxic chemicals are created (O2.-, H2O2, HClO) kill more bacteria with toxic chemicals than phagocytosis

24 Eosinophils Found mucous membranes
Defend mainly against parasites, allergens kill tapeworms and roundworms by producing superoxide, hydrogen peroxide, and toxic proteins promote action of basophils and mast cells phagocytize antigen-antibody complexes limit action of histamine and other inflammatory chemicals

25 Basophils secrete chemicals that aid mobility and action of WBC other leukocytes leukotrienes – activate and attract neutrophils and eosinophils histamine – a vasodilator which increases blood flow speeds delivery of leukocytes to the area heparin – inhibits the formation of clots would impede leukocyte mobility mast cells also secrete these substances type of connective tissue cell very similar to basophils

26 Monocytes monocytes - emigrate from blood into the connective tissue and transform into macrophages macrophage system – all the body’s avidly phagocytic cells, except leukocytes wandering macrophages – actively seeking pathogens widely distributed in loose connective tissue fixed macrophages – phagocytize only pathogens that come to them microglia – in central nervous system alveolar macrophages – in lungs hepatic macrophages – in liver

27 Antimicrobial Proteins
proteins that inhibit microbial reproduction and provide short-term, nonspecific resistance to pathogenic bacteria and viruses two families of antimicrobial proteins: interferons complement system

28 Complement System complement system – a group of 30 or more globular proteins that make powerful contributions to both nonspecific resistance and specific immunity activated complement brings about four methods of pathogen destruction inflammation immune clearance phagocytosis cytolysis three routes of complement activation classical pathway alternative pathway lectin pathway

29 Complement System classical pathway alternative pathway lectin pathway
requires antibody molecule to get started thus part of specific immunity antibody binds to antigen on surface of the pathogenic organism forms antigen-antibody (Ag-Ab) complex changes the antibody’s shape exposing a pair of complement-binding sites binding of complement (C1) sets off a reaction cascade called complement fixation results in a chain of complement proteins attaching to the antibody alternative pathway nonspecific, do not require antibody C3 breaks down in the blood to C3a and C3b C3b binds directly to targets such as human tumor cells, viruses, bacteria, and yeasts triggers cascade reaction with autocatalytic effect where more C3 is formed lectin pathway lectins – plasma proteins that bind to carbohydrates bind to certain sugars of a microbial cell surface sets off another cascade of C3 production

30 Complement Activation
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Classical pathway (antibody-dependent) Alternative pathway (antibody-independent) Lectin pathway (antibody-independent) C3 dissociates into fragments C3a and C3b Antigen–antibody complexes form on pathogen surface Lectin binds to carbohydrates on pathogen surface C3b binds to pathogen surface Reaction cascade (complement fixation) Reaction cascade Reaction cascade and autocatalytic effect C3 dissociates into C3a and C3b Figure 21.15 C3a C3b Binds to basophils and mast cells Stimulates neutrophil and macrophage activity Binds Ag–Ab complexes to RBCs Coats bacteria, viruses, and other pathogens Splits C5 into C5a and C5b C5b binds C6, C7, and C8 Release of histamine and other inflammatory chemicals RBCs transport Ag–Ab complexes to liver and spleen Opsonization C5b678 complex binds ring of C9 molecules Phagocytes remove and degrade Ag–Ab complexes Membrane attack complex Inflammation Immune clearance Phagocytosis Cytolysis Four mechanisms of pathogen destruction

31 Membrane Attack Complex
complement proteins form ring in plasma membrane of target cell causing cytolysis Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. C5b C6 C7 C9 C8 C9 C9 C9 C9 Figure 21.16

32 Immune Surveillance immune surveillance – a phenomenon in which natural (NK) killer cells continually patrol the body on the lookout for pathogens and diseased host cells. natural killer (NK) cells attack and destroy: bacteria, cells of transplanted organs, cells infected with viruses, and cancer cells recognizes enemy cell and binds release proteins called perforins polymerize a ring and create a hole in its plasma membrane secrete a group of protein degrading enzymes – granzymes degrade cellular enzymes and induce apoptosis Macrophage

33 Fever fever – an abnormally elevation of body temperature
pyrexia, febrile results from trauma, infections, drug reactions, brain tumors, and other causes fever is an adaptive defense mechanism, in moderation, does more good than harm promotes interferon activity elevates metabolic rate and accelerates tissue repair inhibits reproduction of bacteria and viruses initiation of fever by exogenous pyrogens – fever producing agents glycolipids on bacterial and viral surfaces attacking neutrophils and macrophages secrete endogenous pyrogens stimulate neurons in anterior hypothalamus to secrete prostaglandin E2 PGE2 raises hypothalamic set point for body temperature stages of fever onset, stadium, defervescence

34 Course of a Fever Figure 21.18 39 5 Infection ends, set point returns
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 39 5 Infection ends, set point returns to normal 4 Stadium (body temperature oscillates around new set point) 38 3 Onset (body temperature rises) Temperature (°C) 6 Defervescence (body temperature returns to normal) 2 Hypothalamic thermostat is reset to higher set point 37 Normal body temperature 1 Infection and pyrogen secretion Figure 21.18

35 Reye Syndrome Reye Syndrome – serious disorder in children younger than 15 following an acute viral infection such as chicken pox or influenza swelling of brain neurons fatty infiltration of liver and other viscera pressure of swelling brain nausea, vomiting, disorientation, seizures and coma 30% die, survivors sometimes suffer mental retardation can be triggered by the use of aspirin to control fever never give aspirin to children with chickenpox or flulike symptoms

36 Inflammation inflammation – local defensive response to tissue injury of any kind, including trauma and infection general purposes of inflammation limit spread of pathogens, then destroys them remove debris from damaged tissue initiate tissue repair four cardinal signs of inflammation - redness - swelling - heat - pain

37 Inflammation suffix -itis denotes inflammation of specific organs: arthritis, pancreatitis, dermatitis cytokines – class of chemicals that regulate inflammation and immunity secreted mainly by leukocytes alter the physiology or behavior of receiving cell act at short range, neighboring cells (paracrines) or the same cell that secretes them (autocrines) include interferon, interleukins, tumor necrosis factor, chemotactic factors, and others

38 Processes of Inflammation
three major processes of inflammation mobilization of body defenses Hyperemia Vasodilation containment and destruction of pathogens Fibrinogen Heparin Neutrophils attracted by chemotaxis tissue cleanup and repair Monocytes arrive in 8-12 hours Edema Platelet-derived growth factor

39 Mobilization of Defenses
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. leukocyte behavior margination selectins cause leukocytes to adhere to blood vessel walls diapedesis (emigration) leukocytes squeeze between endothelial cells into tissue space Splinter From damaged tissue 1 Inflammatory chemicals Bacteria From mast cells 5 Phagocytosis From blood 4 Chemotaxis Mast cells Increased permeability 3 Diapedesis 2 Neutrophils Margination Blood capillary or venule Figure 21.19

40 Specific Immunity immune system – composed of a large population of widely distributed cells that recognize foreign substances and act to neutralize or destroy them two characteristics distinguish immunity from nonspecific resistance specificity – immunity directed against a particular pathogen memory – when re-exposed to the same pathogen, the body reacts so quickly that there is no noticeable illness two types of immunity cellular (cell-mediated) immunity: (T cells) lymphocytes directly attack and destroy foreign cells or diseased host cells rids the body of pathogens that reside inside human cells, where they are inaccessible to antibodies kills cells that harbor them humoral (antibody-mediated) immunity: (B cells) mediated by antibodies that do not directly destroy a pathogen indirect attack where antibodies assault the pathogen can only work against the extracellular stage of infectious microorganisms

41 Passive and Active Immunity
natural active immunity production of one’s own antibodies or T cells as a result of infection or natural exposure to antigen artificial active immunity production of one’s own antibodies or T cells as a result of vaccination against disease natural passive immunity temporary immunity that results from antibodies produced by another person fetus acquires antibodies from mother through placenta, milk artificial passive immunity temporary immunity that results from the injection of immune serum (antibodies) from another person or animal treatment for snakebite, botulism, rabies, tetanus, and other diseases

42 Antigens Antigen – any molecule that triggers an immune response
Large molecular weights of over 10,000 amu Proteins, polysaccharides, glycoproteins, glycolipids Epitopes (antigenic determinants) – certain regions of an antigen molecule that stimulate immune responses Haptens - to small to be antigenic in themselves must combine with a host macromolecule create a unique complex that the body recognizes as foreign cosmetics, detergents, industrial chemicals, poison ivy, and animal dander

43 Lymphocytes major cells of the immune system
macrophages dendritic cells especially concentrated in strategic places such as lymphatic organs, skin, and mucous membranes three categories of lymphocytes natural killer (NK) cells – immune surveillance T lymphocytes (T cells) B lymphocytes (B cells)

44 Life Cycle of T cells Self tolerance and positive selection Deployment
‘Born’ in the red bone marrow descendant of PPSCs, released into blood, colonize thymus Mature in thymus thymosins stimulate maturing T cells to develop surface antigen receptors with receptors in place, the T cells are now immunocompetent – capable of recognizing antigens presented to them by APCs Tested by reticuloendothelial cells, present ‘self’ antigens to them two ways to fail the test: inability to recognize the RE cells, especially their MHC antigens would be incapable of recognizing a foreign attack on the body reacting to the self antigen T cells would attack one’s own tissues Negative selection Clonal deletion Anergy Self tolerance and positive selection Naïve T-cells Deployment Leave thymus, colonize lymphatic tissues and organs

45 B Lymphocytes (B cells)
site of development group fetal stem cells remain in bone marrow develop into B cells B cell selection B cells that react to self antigens undergo either anergy or clonal deletion same as T cell selection self-tolerant B cells synthesize antigen surface receptors, divide rapidly, produce immunocompetent clones leave bone marrow and colonize same lymphatic tissues and organs as T cells

46 Antigen-Presenting Cells (APCs)
T cells can not recognize their antigens on their own Antigen-presenting cells (APCs) are required to help dendritic cells, macrophages, reticular cells, and B cells function as APCs Function of APCs depends on major histocompatibility complex (MHC) proteins act as cell ‘identification tags’ that label every cell of your body as belonging to you structurally unique for each individual, except for identical twins Antigen processing APC encounters antigen internalizes it by endocytosis and digests displays epitopes in grooves of the MHC protein Antigen presenting Wander T cell detects an APC with a nonself-antigen, immune attack initiated Communicate via interleukins

47 Antigen Processing Figure 21.21a 1 Phagocytosis of antigen Lysosome
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 1 Phagocytosis of antigen Lysosome Epitopes MHC protein 2 Lysosome fuses with phagosome Phagosome 6 Processed antigen fragments (epitopes) displayed on macrophage surface 3 Antigen and enzyme mix in phagolysosome 4 Antigen is degraded Figure 21.21a 5 Antigen residue is voided by exocytosis (a)

48 Cellular Immunity cellular (cell-mediated) immunity – a form of specific defense in which the T lymphocytes directly attack and destroy diseased or foreign cells, and the immune system remembers the antigens and prevents them from causing disease in the future both cellular and humoral immunity occur in three stages: recognition attack memory

49 Cellular Immunity cellular immunity involves four classes of T cells
cytotoxic T (TC) cells – killer T cells (T8, CD8, or CD8+) the ‘effectors’ of cellular immunity carry out attack on enemy cells helper T (TH) cells (T4, CD4, CD4+) help promote TC cell and B cell action and nonspecific resistance regulatory T (TR) cells – T-regs inhibit multiplication and cytokine secretion by other T cells limit immune response memory (TM) cells descend from the cytotoxic T cells responsible for memory in cellular immunity

50 T Cell Recognition antigen presentation
recognition phase has two aspects: antigen presentation and T cell activation antigen presentation APC encounters and processes an antigen migrates to nearest lymph node displays it to the T cells when T cell encounters its displayed antigen on the MHC protein, they initiate the immune response T cells respond to two classes of MHC proteins MHC – I proteins occur on every nucleated cells in the body constantly produced by our cells, transported to, and inserted on plasma membrane normal self antigens that do not elicit and T cell response viral proteins or abnormal cancer antigens do elicit a T cell response infected or malignant cells are then destroyed before they can do further harm to the body MHC – II proteins (human leukocyte antigens – HLAs) occur only on APCs and display only foreign antigens TC cells respond only to MHC – I proteins TH cells respond only to MHC – II proteins

51 T cell Activation Figure 21.22
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. APC Costimulation protein MHC protein Antigen 1 Antigen recognition TC or TH APC TC or TH 2 Costimulation TC TH TM or TH TC TC TM TM TH 3 Clonal selection Memory T cells Effector cells TC TH Figure 21.22 MHC-II protein MHC-I protein 4 Lethal hit 4 Interleukin secretion Enemy cell APC or Destruction of enemy cell Activity of NK, B, or TC cells Development of memory T cells Inflammation and other nonspecific defenses

52 Attack : Role of Helper T (TH) Cells
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Macrophage, B cell, or other antigen-presenting cell Helper T (T4) cell Macrophage- activating factor Other cytokines Interleukin-2 Other cytokines Interleukin-1 Other cytokines Figure 21.23 Macrophage activity Leukocyte chemotaxis Inflammation Clonal selection of B cells Clonal selection of cytotoxic T cells Nonspecific defense Humoral immunity Cellular immunity

53 Attack : Cytotoxic T (TC) Cells
cytotoxic T (TC) cell are the only T cells directly attack other cells when TC cell recognizes a complex of antigen and MHC – I protein on a diseased or foreign cell it ‘docks’ on that cell delivers a lethal hit of toxic chemicals perforin and granzymes – kill cells in the same manner as NK cells interferons – inhibit viral replication recruit and activate macrophages tumor necrosis factor (TNF) – aids in macrophage activation and kills cancer cells goes off in search of another enemy cell while the chemicals do their work

54 Cytotoxic T Cell Function
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. T cell T cell Cancer cell Dying cancer cell (a) 10 µm (b) Figure a-b Dr. Andrejs Liepins cytotoxic T cell binding to cancer cell

55 Memory immune memory follows primary response
following clonal selection, some TC and TH cells become memory cells long-lived more numerous than naïve T cells fewer steps to be activated, so they respond more rapidly T cell recall response upon re-exposure to same pathogen later in life, memory cells launch a quick attack so that no noticeable illness occurs the person is immune to the disease

56 Humoral Immunity humoral immunity is a more indirect method of defense than cellular immunity B lymphocytes of humoral immunity produce antibodies that bind to antigens and tag them for destruction by other means cellular immunity attacks the enemy cells directly works in three stages like cellular immunity recognition attack memory

57 Humoral Immunity recognition attack memory
immunocompetent B cell has thousands of surface receptors for one antigen activation begins when an antigen binds to several of these receptors usually B cell response goes no further unless a helper T cell binds to this Ag-MHCP complex bound TH cell secretes interleukins that activate B cell triggers clonal selection B cell mitosis gives rise to an entire battalion of identical B cells programmed against the same antigen most differentiate into plasma cells larger than B cells and contain an abundance of rough ER secrete antibodies at a rate of 2,000 molecules per second during their life span of 4 to 5 days antibodies travel through the body in the blood or other body fluids first exposure antibodies IgM, later exposures to the same antigen, IgG attack antibodies bind to antigen, render it harmless, ‘tag it’ for destruction memory some B cells differentiate into memory cells

58 Humoral Immunity - Recognition
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Antigen Receptor Lymphocyte 1 Antigen recognition Immunocompetent B cells exposed to antigen. Antigen binds only to B cells with complementary receptors. Helper T cell 2 Antigen presentation B cell internalizes antigen and displays processed epitope. Helper T cell binds to B cell and secretes interleukin. Epitope B cell MHC-II protein Interleukin 3 Clonal selection Interleukin stimulates B cell to divide repeatedly and form a clone. 4 Differentiation Some cells of the clone become memory B cells. Most differentiate into plasma cells. Plasma cells Memory B cell Figure 21.25 5 Attack Plasma cells synthesize and secrete antibody. Antibody employs various means to render antigen harmless. Antibody

59 B cells and Plasma cells
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Rough endoplasmic reticulum Mitochondria Nucleus (a) B cell 2 µm (b) Plasma cell 2 µm © Dr. Don W. Fawcett/Visuals Unlimited Figure a-b

60 Antibodies immunoglobulin (Ig) – an antibody is a defensive gamma globulin found in the blood plasma, tissue fluids, body secretions, and some leukocyte membranes antibody monomer – the basic structural unit of an antibody

61 Five Classes of Antibodies
named for the structure of their C region IgA - monomer in plasma; dimer in mucus, saliva, tears, milk, and intestinal secretions prevents pathogen adherence to epithelia and penetrating underlying tissues provides passive immunity to newborns IgD - monomer; B cell transmembrane antigen receptor thought to function in B cell activation by antigens IgE - monomer; transmembrane protein on basophils and mast cells stimulates release of histamine and other chemical mediators of inflammation and allergy attracts eosinophils to parasitic infections produces immediate hypersensitivity reactions IgG - monomer; constitutes 80% of circulating antibodies crosses placenta to fetus, secreted in secondary immune response, complement fixation IgM – pentamer in plasma and lymph secreted in primary immune response, agglutination, complement fixation

62 Humoral Immunity - Attack
neutralization antibodies mask pathogenic region of antigen complement fixation antigen binds to IgM or IgG, antibody changes shape, initiates complement binding which leads to inflammation, phagocytosis, immune clearance, or cytolysis primary defense against foreign cells, bacteria, and mismatched RBCs agglutination antibody has 2-10 binding sites; binds to multiple enemy cells immobilizing them from spreading precipitation antibody binds antigen molecules (not cells); creates antigen-antibody complex that precipitates, phagocytized by eosinophils

63 Agglutination and Precipitation
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Antibodies (IgM) (a) Figure a-b Antigens Antibody monomers (b)

64 Humoral Immunity - Memory
primary immune response – immune reaction brought about by the first exposure to an antigen appearance of protective antibodies delayed for 3 to 6 days while naïve B cells multiply and differentiate into plasma cells as plasma cells produce antibodies, the antibody titer (level in the blood plasma) rises IgM appears first, peaks in about 10 days, soon declines IgG levels rise as IgM declines, but IgG titer drops to a low level within a month primary response leaves one with an immune memory of the antigen during clonal selection, some of the clone becomes memory B cells found mainly in germinal centers of the lymph nodes mount a very quick secondary (anamnestic) response

65 Humoral Immunity Responses
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Primary response Secondary response IgG Serum antibody titer IgG IgM IgM 5 10 15 20 25 5 10 15 20 25 Days from first exposure to antigen Days from reexposure to same antigen Figure 21.29

66 Immune System Disorders
immune response may be: too vigorous too weak misdirected against wrong targets

67 Hypersensitivity hypersensitivity – an excessive immune reaction against antigens that most people tolerate includes: alloimmunity - reaction to transplanted tissue from another person autoimmunity - abnormal reactions to one’s own tissues allergies – reactions to environmental antigens (allergens) – dust, mold, pollen, vaccines, bee and wasp venom, poison ivy and other plants, foods such as nuts, milk, eggs, and shellfish, drugs such as penicillin, tetracycline, and insulin four kinds of hypersensitivity based on the type of immune agents involved (antibodies or T cells) and their method of attack on the antigen Type I acute (immediate) hypersensitivity – very rapid response Type II and Type III - subacute – slower onset (1 – 3 hours after exposure) last longer (10 – 15 hours) Types I, II, and III are quicker antibody mediated responses Type IV - delayed cell-mediated response

68 Type I (acute) Hypersensitivity
includes most common allergies IgE-mediated reaction that begins within seconds of exposure usually subsides within 30 minutes, although it can be severe to fatal allergens bind to IgE on the membranes of basophils and mast cells stimulate them to secrete histamine and other inflammatory and vasoactive chemicals chemicals trigger glandular secretion, vasodilation, increased capillary permeability, smooth muscle spasms, and other effects clinical signs include: local edema, mucus hypersecretion and congestion, watery eyes, runny nose, hives, and sometimes cramps, diarrhea and vomiting examples: food allergies and asthma – local inflammatory reaction to inhaled allergens

69 Type I (acute) Hypersensitivity
anaphylaxis immediate, severe reaction Type I reaction local anaphylaxis can be relieved with antihistamines anaphylactic shock severe, widespread acute hypersensitivity that occurs when an allergen is introduced to the bloodstream of an allergic individual characterized by bronchoconstriction, dyspnea (labored breathing), widespread vasodilation, circulatory shock, and sometimes death antihistamines are inadequate by themselves epinephrine relieves the symptoms by dilating bronchioles, increasing cardiac output, and restoring blood pressure fluid therapy and respiratory support are sometimes required

70 Type I (acute) Hypersensitivity
asthma most common chronic illness in children allergic (extrinsic) asthma is most common form respiratory crisis triggered by inhaled allergens stimulate plasma cells to secrete IgE binds to most cells in respiratory mucosa mast cells release a complex mixture of inflammatory chemicals triggers intense airway inflammation nonallergic (intrinsic) asthma triggered by infections, drugs, air pollutants, cold dry air, exercise or emotions more common in adults, but effects are the same

71 Type I (acute) Hypersensitivity
asthma effects: bronchospasms within minutes severe coughing, wheezing, and sometimes fatal suffocation second respiratory crisis often occurs 6 to 8 hours later interleukins attract eosinophils to bronchial tissue secrete proteins that paralyze respiratory cilia severely damage epithelium leading to scarring and long-term damage to the lungs bronchioles become edematous and plugged with thick, sticky mucous treatment epinephrine and other β-adrenergic stimulants to dilate airway and restore breathing, and with inhaled corticosteroids to minimize inflammation and long term damage

72 Type II Hypersensitivity (Antibody-Dependent Cytotoxic)
occurs when IgG or IgM attacks antigens bound to cell surfaces reaction leads to complement activation and lysis or opsonization of the target cell macrophages phagocytize and destroy opsonized platelets, erythrocytes, or other cells examples: blood transfusion reaction, pemphigus vulgaris, and some drug reactions

73 Type III Hypersensitivity (Immune Complex)
occurs when IgG or IgM form antigen-antibody complexes precipitate beneath endothelium of blood vessels and other tissues at site, activate complement and trigger intense inflammation examples: autoimmune diseases - acute glomerulonephritis and in systemic lupus erythematosus, a widespread inflammation of the connective tissues

74 Type IV Hypersensitivity (Delayed)
cell-mediated reaction in which the signs appear 12 to 72 hour after exposure begins with APCs in lymph nodes display antigens to helper T cells T cells secrete interferon and cytokines that activate cytotoxic T cells and macrophages result is a mixture of nonspecific and immune responses examples: haptens in cosmetics and poison ivy, graft rejection, TB skin test, beta cell destruction that causes type I diabetes mellitus

75 Autoimmune Diseases autoimmune diseases - failures of self-tolerance
immune system fails to distinguish self-antigens from foreign ones produces autoantibodies that attack the body’s own tissues three reasons why self-tolerance cross-reactivity some antibodies against foreign antigens react to similar self-antigens rheumatic fever - streptococcus antibodies also react with heart valves abnormal exposure of self-antigens in the blood some of our native antigens are not exposed to blood blood-testes barrier isolates sperm from blood changes in structure of self-antigens viruses and drugs may change the structure of self-antigens or cause the immune system to perceive them as foreign self-reactive T cells not all are eliminated in thymus and are normally kept in check by regulatory T (TR) cells

76 Immunodeficiency Diseases
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. immune system fails to react vigorously enough Severe Combined Immunodeficiency Disease (SCID) hereditary lack of T and B cells vulnerability to opportunistic infection and must live in protective enclosures © Science VU/Visuals Unlimited Figure 21.30

77 Immunodeficiency Diseases
Acquired Immunodeficiency Syndrome (AIDS) – nonhereditary diseases contracted after birth group of conditions that involve and severely depress the immune response caused by infection with the human immunodeficiency virus (HIV) HIV structure (next slide) invades helper T cells, macrophages and dendritic cells by “tricking” them to internalize viruses by receptor mediated endocytosis reverse transcriptase (retrovirus) uses viral RNA as template to synthesize DNA new DNA inserted into host cell DNA (may be dormant for months to years) when activated, it induces the host cell to produce new viral RNA, capsid proteins, and matrix proteins they are coated with bits of the host cell’s plasma membrane adhere to new host cells and repeat the process

78 HIV Structure Figure 21.31a Envelope: Glycoprotein Phospholipid Matrix
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Envelope: Glycoprotein Phospholipid Matrix Capsid RNA Reverse transcriptase (a) Figure 21.31a

79 AIDS by destroying TH cells, HIV strikes at the central coordinating agent of nonspecific defense, humoral immunity, and cellular immunity incubation period ranges from several months to 12 years signs and symptoms early symptoms: flulike symptoms of chills and fever progresses to night sweats, fatigue, headache, extreme weight loss, lymphadenitis normal TH count is 600 to 1,200 cells/L of blood, but in AIDS it is less than 200 cells/L person susceptible to opportunistic infections (Toxoplasma, Pneumocystis, herpes simplex virus, cytomegalovirus, or tuberculosis) Candida (thrush): white patches on mucous membranes Kaposi sarcoma: cancer originates in endothelial cells of blood vessels causes purple lesions in skin

80 © Roger Ressmeyer/Corbis
Kaposi Sarcoma Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. © Roger Ressmeyer/Corbis Figure 21.32

81 HIV Transmission through blood, semen, vaginal secretions, breast milk, or across the placenta most common means of transmission sexual intercourse (vaginal, anal, oral) contaminated blood products contaminated needles not transmitted by casual contact undamaged latex condom is an effective barrier to HIV, especially with spermicide nonoxynol-9

82 Treatment Strategies prevent binding to CD4 proteins of TH cells
disrupt reverse transcriptase to inhibit assembly of new viruses or their release from host cells medications none can eliminate HIV, all have serious side-effects HIV develops drug resistance medicines used in combination AZT (azidothymidine) first anti-HIV drug - inhibits reverse transcriptase protease inhibitors inhibit enzymes HIV needs to replicate now more than 24 anti-HIV drugs on the market

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